Anti-Thyroid Peroxidase Reactivity Is Heightened in Pemphigus Vulgaris and Is Driven by Human Leukocyte Antigen Status and the Absence of Desmoglein Reactivity.

Kristina Seiffert-Sinha,Animesh A Sinha,John A Gerlach,Shahzaib Khan,Kristopher Attwood

doi:10.3389/fimmu.2018.00625

Kristina Seiffert-Sinha, Animesh A Sinha + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2018.00625

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Abstract

Pemphigus vulgaris (PV) belongs to an autoimmune disease cluster that includes autoimmune thyroid disease (AITD), suggesting common mechanisms driving autoimmune susceptibility. Our group has shown that PV patients exhibit significant reactivity to AITD-related anti-thyroid peroxidase (anti-TPO), and anti-TPO antibodies affect signaling pathways in keratinocytes similar to anti-desmoglein (Dsg) 3 antibodies. To further assess the relevance of anti-TPO reactivity in PV, we analyzed anti-TPO levels in 280 PV and 167 healthy control serum samples across a comprehensive set of variable and static parameters of disease activity and etiopathogenesis. PV patients have significantly higher activity rates (A.R.s) for anti-TPO than healthy controls, but levels do not differ between phases of clinical activity and remission. Patients that carry both the PV-associated human leukocyte antigen (HLA) alleles DRB1*0402 and DQB1*0503, or DQB1*0503 alone show a low prevalence of anti-TPO (A.R. 9.5 and 4.8%, respectively), while patients that lack expression of these alleles or carry DRB1*0402 alone have a much higher prevalence of anti-TPO (A.R. 23.1 and 15.8%, respectively), suggesting that the absence of DQB1*0503 may predispose patients to the development of anti-TPO antibodies. Similarly, anti-Dsg1−/3− patients have a higher anti-TPO A.R. (26.9%) than anti-Dsg1−/3+ (18.8%), anti-Dsg1+/3− (14.3%), and anti-Dsg1+/3+ (3.9%) patients. Our data suggest that anti-TPO reactivity in PV is driven by genetic markers that may be in linkage disequilibrium with the established PV-susceptibility alleles and that this association drives the selection of a combination of anti-Dsg and anti-TPO antibodies, with anti-TPO filling the gap in active patients that do not carry the established PV-associated autoantibodies and/or are lacking the established PV-HLA-susceptibility alleles.

Highlights

It is well accepted that numerous autoimmune diseases can co-exist within individuals or certain families, a concept known as autoimmune diathesis [1, 2]
We previously examined the self-reported co-existence of other autoimmune conditions in pemphigus vulgaris (PV) patients and found autoimmune thyroid disease (AITD) to be the leading comorbidity in three independent studies [4, 8, 10]
Among PV patients that did not report a history of thyroid disease (n = 177), 12.99% (n = 23) were found to still carry autoantibodies directed against either/ or anti-thyroid peroxidase (TPO) and anti-Tg, albeit with considerably lower levels of anti-Tg (3.95%, n = 7)

Summary

Introduction

It is well accepted that numerous autoimmune diseases can co-exist within individuals or certain families, a concept known as autoimmune diathesis (a broad genetic predisposition to develop autoimmune disease) [1, 2]. Among the autoimmune diseases found in PV patients and/or their family members, autoimmune thyroid disease (AITD) is the most common, followed by rheumatoid arthritis (RA) and diabetes mellitus type I [4, 10, 11]. These data indicate that PV belongs to an established autoimmune disease cluster comprised of AITD, RA and type I diabetes, suggesting the possibility of common genetic elements across clinically distinct diseases that might underlie autoimmune susceptibility [4, 8]. The broader impact of PV-associated HLA alleles in the development of the spectrum of PV-associated autoantibodies is not known

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